Biodegradable block copolymeric compositions for drug delivery

Abstract

An improved drug delivery composition and method of use is disclosed. The composition comprises one or more biodegradable block copolymer drug carriers; and a reconstitution enhancing and enabling agent comprising polyethylene glycol (PEG), a PEG derivative or a mixture of PEG and a PEG derivative. The composition can be administered as is or after being be dissolved or rapidly reconstituted in an aqueous vehicle to afford a homogeneous solution or uniform colloidal systems.

We claim: 
     
       1. A method of preparing an improved drug delivery formulation comprising the steps of:
 (a) providing a drug delivery composition comprising:
 (1) one or more biodegradable block copolymer drug carriers comprising A-B, A-B-A or B-A-B block copolymers having a total weight average molecular weight of 2400 to 4999 Daltons,
 wherein the A block is a biodegradable polyester or poly(ortho ester) and the B block is polyethylene glycol (PEG), and 
 wherein the weight percentage of the A block is between 50.1% to 65% and the weight percentage of the B block is between 35% to 49.9%, 
 wherein said block copolymer, when formed as an aqueous polymer solution, remains a free flowing liquid upon parenteral administration; and 
 
 (2) a liquid polyethylene glycol (PEG), a PEG derivative, or a mixture of PEG and a PEG derivative,
 wherein said PEG or PEG derivative has a molecular weight of 150 to 1100 Daltons; 
 
 wherein the biodegradable block copolymeric drug carrier is soluble in the liquid PEG, PEG derivatives, or mixtures of PEG and PEG derivatives,
 wherein the PEG derivative is an ester derivatized PEG wherein the PEG is derivatized from D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyric acids, malic acid, or a mixture thereof; and 
 
 wherein the weight ratio of the biodegradable block copolymeric drug carrier and the PEG, PEG derivative, or mixtures thereof is within the range of 5:1 to 1:99, 
 wherein the composition is reconstituted in water or an aqueous solution to form a homogeneous solution or an uniform colloidal system within 0.01 minutes to 180 minutes, 
 
 (b) formulating the composition as an injectable liquid which is without water, by mixing with water, or mixing an aqueous solution with the composition to form a homogeneous aqueous solution or a uniform colloidal system. 
 
     
     
       2. The method of  claim 1 , wherein the ratio of the composition to water or aqueous solution is within the range of 2:1 to 1:10,000. 
     
     
       3. The method of  claim 1 , wherein said composition is formulated as an injectable liquid comprising mixing said composition with water to form a homogeneous aqueous solution. 
     
     
       4. The method of  claim 3 , wherein said method further comprises adding a solubilized drug. 
     
     
       5. The method of  claim 4 , wherein said solubilzed drug is paclitacxel. 
     
     
       6. The method of  claim 1 , wherein the PEG derivative is an ortho ester derivatized PEG. 
     
     
       7. A method of preparing an improved drug delivery formulation comprising the steps of:
 (a) providing a drug delivery composition comprising:
 (1) one or more biodegradable block copolymer drug carriers comprising A-B, A-B-A or B-A-B block copolymers having a total weight average molecular weight of 2000 to 4990 Daltons,
 wherein the A block is a biodegradable polyester or poly(ortho ester) and the B block is polyethylene glycol (PEG), and 
 wherein the weight percentage of the A block is between 51% to 83% and the weight percentage of the B block is between 17% to 49%; and 
 
 (2) a polyethylene glycol (PEG), a PEG derivative, or a mixtures of PEG and a PEG derivative,
 wherein said PEG or PEG derivative has a molecular weight of 150 to 1100 Daltons; wherein the PEG derivative is an ester derivatized PEG and wherein the PEG is derivatized with D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyric acids, malic acid, or mixtures thereof, and 
 
 
 wherein at least one of the biodegradable block copolymeric drug carriers is soluble in an aqueous solution and miscible with the PEG, PEG derivatives, or mixtures thereof, and wherein the weight ratio of component (1) to component (2) is within the range of 2:1 to 1:99, and 
 (b) formulating the composition as an injectable liquid which is without water, by mixing with water or mixing an aqueous solution with the composition to form a homogeneous aqueous solution or a uniform colloidal system,
 wherein the composition is free of toxic or dangerous organic solvents, and the composition possesses reverse thermal gelation properties such that it forms a gel when reconstituted and administered to a warm blooded mammal. 
 
 
     
     
       8. The method of  claim 7 , wherein the ratio of the composition to water or aqueous solution is within the range of 2:1 to 1:10,000. 
     
     
       9. The method of  claim 7 , wherein the composition is reconstituted in water or an aqueous solution to form a homogeneous solution or an uniform colloidal system within 0.01 minutes to 180 minutes. 
     
     
       10. The method of  claim 7 , wherein said method further comprises adding a solubilized drug. 
     
     
       11. The method of  claim 10 , wherein said solubilzed drug is paclitacxel. 
     
     
       12. The method of  claim 7 , wherein the PEG derivative is an ortho ester derivatized PEG. 
     
     
       13. A method of preparing an improved drug delivery formulation comprising the steps of: providing a drug delivery composition comprising:
 (1) one or more biodegradable block copolymer drug carriers comprising A-B, A-B-A or B-A-B block copolymers having a total weight average molecular weight of 2000 to 4990 Daltons,
 wherein the A block is a biodegradable polyester or poly(ortho ester) and the B block is polyethylene glycol (PEG), and 
 wherein the weight percentage of the A block is between 51% to 83% and the weight percentage of the B block is between 17% to 49%; and 
 
 (2) a liquid polyethylene glycol (PEG), a PEG derivative, or a mixtures of PEG and a PEG derivative,
 wherein said PEG or PEG derivative has a molecular weight of 150 to 1100 Daltons; 
 
 wherein the biodegradable block copolymeric drug carrier is water insoluble but is soluble in the liquid PEG, a PEG derivative, or a mixtures of PEG and a PEG derivative; and 
 (3) formulating the composition as an injectable liquid without adding water; wherein the PEG derivative is an ester derivatized PEG wherein the PEG is derivatized from D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxy butyric acid, 8-valerolactone. 
 
     
     
       14. The method of  claim 13 , wherein said method further comprises adding a solubilized drug. 
     
     
       15. The method of  claim 14 , wherein said solubilzed drug is paclitacxel. 
     
     
       16. The method of  claim 13 , wherein the PEG derivative is an ortho ester derivatized PEG.